With regard to natural vitamins showing a high biologically effective value, there are D2 (ergocalciferol) and D3 (cholecalciferol) and physiological actions of those vitamin D derivatives in human body are same. Those vitamin D derivatives are synthesized in human skin by action of ultraviolet ray and their structures change in kidney and liver to give active-form vitamin D derivatives whereby a physiological action is firstly achieved. The active-form vitamin D is a kind of hormone and its action mechanism is similar to a steroid hormone. Thus, it is bonded to a receptor existing in cell nucleus and controls the transcription of specific genes whereupon the activity is finally achieved.
With regard to 1α,25-dihydroxyvitamin D3 which is an active-form vitamin D, many structural analogs have been prepared and their activities have been tested already. Some of those compounds show a significant effect concerning cell differentiation and calcium adjustment and, therefore, they have been known to be useful for the treatment of various diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis and cancer.
A novel group of vitamin D analogs where an exo-methylene group (C-19) specific to vitamin D derivatives is substituted with two hydrogen atoms or 19-nor-vitamin D derivatives such as 1α,25-dihydroxy-19-nor-vitamin D3 have been prepared and their biological test has been conducted already. It has been clarified that those compounds show a selective activity profile and a very low calcium transfer activity having a high efficacy for induction of cell differentiation. Therefore, those compounds have been proposed as treating agents not only for malignant tumor, leukemia, cancer, cancer of the colon, breast cancer and prostatic cancer but also for osteomalacia, senile osteoporosis, postmenopausal osteoporosis, steroid-induced osteoporosis, osteoporosis due to low turnover of bone, renal osteodystrophy, psoriasis, imbalance of immune system, multiple sclerosis, diabetes mellitus, refusal for transplantation or various skin disorders (Japanese Patent Laid-Open No. 05/186,421, U.S. Pat. No. 5,086,191, WO 01/92221, WO 02/05823, WO 01/74765, WO 02/20021, WO 01/74766, WO 02/05824, WO 00/10548, WO 01/03704, WO 01/72292, etc.).
The desired 19-nor-vitamin D derivatives are prepared by the reaction of Windaus Grudman ketone with phosphine oxide in the presence of a base followed, if necessary, by removing the protective group. Here, phosphine oxide is synthesized via many steps using quinic acid as a starting material (the reaction step formula 1 in Japanese Patent Laid-Open No. 05/186,421).
Recently, compounds in which 2-position of 1α,25-dihydroxy-19-nor-vitamin D3 is substituted with hydroxyl group or an alkoxy group has been synthesized as well (U.S. Pat. No. 5,536,713).
In addition, 2-alkylidene-19-nor-vitamin D compounds, particularly 2-methylene-19-nor-vitamin D compounds, having an alkylidene group (particularly, methylene group) at 2-position where an exoalkylidene group of A ring of 1α,25-dihydroxy-vitamin D3 is transferred from carbon 10 (C-10) to carbon 2 (C-2) has been receiving public attention since the relatively small alkylidene (particularly, methylene) group at C-2 does not inhibit a vitamin D receptor (Japanese Patent Laid-Open No. 2001/504,135). This compound is also able to be synthesized by the reaction of Windaus Grudman ketone with phosphine oxide having a methylene group at C-2 in the presence of a base followed, if necessary, by removing the protective group. Here, the phosphine oxide having a methylene group at C-2 is also able to be synthesized via many steps using quinic acid as a starting material (scheme I of Japanese Patent Laid-Open No. 2001/504,135).
However, in the above-mentioned method, quinic acid which is expensive is used and, therefore, cost of the synthesized vitamin D derivative also becomes high. Therefore, there has been a demand for the synthesis of vitamin D derivatives from less expensive materials.